The invention relates to an isolated nucleic acid molecule that includes a tau gene sequence, wherein the tau gene sequence contains a mutation linked to a Tau pathology.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is characterized clinically by behavioral, cognitive, and motor disturbance. Historically, many cases of this disease have been described as Pick""s disease. In the majority of families described to date, personality change is the presenting symptom, with initial behavioral changes accompanied by progressive cognitive impairment and sometimes parkinsonism. At autopsy, all patients with FTDP-17 display pronounced fronto-temporal atrophy and neuronal cell loss, gray and white matter gliosis, and superficial cortical spongiform changes. More variably, ballooned neurons, or Pick""s cells, are present. In addition, most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Patients with FTDP-17 do not have Lewy bodies or, crucially, Pick bodies, which distinguishes them from classical Pick""s disease cases. The disease is inherited as an autosomal dominant trait with age dependent penetrance. The age of onset can be highly variable but is usually between the ages of 45-65 years.
The invention is based on the discovery of mutations in the tau gene that are linked to Tau pathologies. Thus, the invention provides nucleic acid molecules that include such mutations, allowing animal models of neurodegenerative diseases to be developed. Identification of the mutations also provides methods for determining a diagnosis of neurodegenerative disease in a patient.
The invention features an isolated nucleic acid molecule including a tau gene sequence, wherein the molecule has a mutation linked to a Tau pathology. The nucleic acid molecule can be from about 15 nucleotides in length to full-length. The mutation can be located in an exon or in an intron. A mutation can be in exon 7, exon 9, exon 10, or in exon 13 and in particular embodiments, at a region encoding amino acids 152, 257, 272, 301, 389, or 406. In one embodiment, the mutation at amino acid 152 is a change from an alanine to a threonine residue, the mutation at amino acid 257 is a change from a lysine to a threonine residue, and the mutation at amino acid 272 is a change from a glycine residue to a valine residue. The mutation at amino acid 301 can be a change from a proline residue to a leucine residue. The mutation at amino acid 389 can be a change from a glycine to an arginine residue. The mutation of amino acid 406 can be a change from an arginine to a tryptophan residue. An additional mutation can include deletion of amino acid 280. The mutation also can be in a splice donor site region and, in a particular embodiment, can destabilize a stem-loop structure of the splice donor site region and can be in a region 13-16 nucleotides 3xe2x80x2 of the exon 10 splice donor site.
The invention also features an isolated polypeptide encoded by a tau nucleic acid molecule of the invention. The polypeptides contain a mutation linked to a Tau pathology. Suitable mutations are described above.
The invention also features a transgenic non-human mammal including a nucleic acid construct. The nucleic acid construct includes a regulatory nucleic acid sequence operably linked to a nucleic acid sequence encoding a Tau polypeptide. Expression of the Tau polypeptide is linked to a Tau pathology in the transgenic non-human mammal. The transgenic non-human mammal can be a rodent, and in particular, a mouse. The regulatory nucleic acid sequence can be a brain-specific promoter. In one embodiment, the Tau polypeptide is human Tau polypeptide, and can be wild-type or can contain a mutation linked to a Tau pathology. The mutation can be, for example, at amino acid 152, 257, 272, 280, 301, 389, or 406. In other embodiments, the transgenic non-human mammal also includes a nucleic acid construct that includes a regulatory sequence operably linked to a nucleic acid sequence encoding a human amyloid precursor protein or a human presenilin-1 protein.
The invention also relates to a method for determining a diagnosis, prognosis, or risk of neurodegenerative disease in a patient. The method includes detecting a tau gene mutation in genomic DNA of the patient, wherein the mutation is linked to a Tau pathology. Mutations that are linked to Tau pathologies are described above.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.